Mechanistic study of glutamine metabolic reprogramming driving non-small cell lung cancer progression via the FGF17-FGFR4 axis mediating epithelial-mesenchymal transition

Introduction The reprogramming of glutamine metabolism holds a pivotal position in the energy provision and biosynthesis of tumors. However, the regulatory mechanism of this phenomenon in non-small cell lung cancer (NSCLC) is still not well-understood. NSCLC is a type of malignancy that has a high incidence and mortality rate globally. There is an urgent need to elucidate the role of glutamine metabolism in its pathological mechanism. This clarification may provide theoretical guidance for developing new therapeutic approaches. Methods Core targets of glutamine metabolism were screened by integrating single-cell transcriptomic and RNA sequencing data from public databases. Target expression was validated in clinical samples by immunohistochemistry (IHC) and Western blot (WB), and its association with clinical features was analyzed. Lentiviral gene silencing was employed to establish glutamine-deprived cell models and xenograft mouse models. To evaluate the effects of the target on cell proliferation, redox balance, and migratory/invasive behavior in cell culture and animal models, we utilized Transwell assays, colony formation assays, redox detection kits, and Seahorse metabolic flux analysis. Subsequently, WB and IHC served to elucidate the downstream pathways and potential synergistic effects of the drugs. Results Analysis of the single-cell atlas revealed a marked increase in epithelial (Epi) cell populations in the tumor milieu of NSCLC. By integrating weighted gene co-expression network analysis (WGCNA) with RNA sequencing, fibroblast growth factor 17 (FGF17) was pinpointed as a crucial regulatory factor. High FGF17 expression showed a strong association with poor prognosis in patient ( p = 0.0078). Consistent clinical data further demonstrated that FGF17 upregulation was associated with higher TNM stages and the presence of lymph node metastasis. Functional and mechanistic analyses revealed that silencing FGF17 suppressed the FGFR4/MEK5/ERK5 signaling cascade, disturbed NRF2-dependent redox homeostasis, and consequently impaired epithelial–mesenchymal transition (EMT), leading to a marked reduction in cancer cell motility and invasiveness. In vivo , targeting FGF17 was shown to synergistically enhance cisplatin antitumor activity and reverse the EMT phenotype. Conclusion As a critical driver of glutamine metabolic reprogramming, FGF17—activated under conditions of GLUL overexpression—stimulates the FGFR4/MEK5/ERK5/NRF2 signaling cascade to maintain redox homeostasis and promote invasion, thereby accelerating NSCLC progression. Targeted intervention of the pathway reverses malignant phenotypes and enhances chemosensitivity. These findings highlight FGF17 as a potential therapeutic target for NSCLC and provide new insights into tumor metabolism and EMT, thereby may paving the way for novel combination therapies.